The use of vasodilators which affect the blood vessels of the gastrointestinal tract to enhance the bioavailability of pharmaceutically active compounds which are subject to passive diffusion absorption from the gastrointestinal tract has not been previously reported in the literature.
The concept of bioavailability is discussed, e.g., in R.D. Hossie et al. (June 1972), "Biopharmaceutical Evaluation of Drug Formulations, Can. Pharm. J. 27/189-- 31/193.
Bioavailability is generally measured using drug-serum concentration-time curves, and includes such factors as rate of entry of the drug into the bloodstream, rate of achieving maximum concentration, and area under the curve. See, e.g., J. Koch Weser (1974), "Bioavailability of Drugs," New Engl. J. Med. 291:233-237. Many factors are known to affect bioavailability of drugs. Such factors include the nature of the form of the drug (ester, salt, complex, etc.); the physical state, particle size and surface area; presence or absence of adjuvants with the drug, type of dosage form in which the drug is administered; and pharmaceutical processes used to make the dosage form. See, e.g., D.E. Cadwallader, (1971) "Biopharmaceutics and Drug Interactions," (Roche Laboratories, Nutley, NJ).
Manipulations of many of these parameters have been reported in the literature as effective means for increasing drug absorption and bioavailability. For example, as regards the physical state of the drug, U.S. Pat. Nos. 4,088,750 and 4,002,718 report increasing bioavailability of digoxin by administering the drug in capsule form. U.S. Pat. No. 4,639,370 reports incorporating a biologically active substance into a water-swellable, water-insoluble polymer. U.S. Pat. Nos. 4,444,769, 4,526,777 and 4,547,498 report special granular formulations of active ingredients, particularly triamterene and hydrochlorothiazide. U.S. Pat. No. 4,562,181 reports an amorphous form of cefuroxime axetil with improved bioavailability. U.S. Pat. Nos. 4,725,429, 4,727,088 and 4,738,956 report a "stick" formulation of benzoyl peroxide for topical application. U.S. Pat. No. 4,758,427 reports the dispersion of psychoactive 2-aryl pyrazolo quinolines in polyvinylpyrrolidone to enhance absorption.
With respect to the use of adjuvants, U.S. Pat. No. 2,899,357 discloses the use of inactive bis-quaternary ammonium alkanes as adjuvants to tie up gastro-intestinal binding sites and allow greater bioavailability of active quaternary ammonium salts. U.S. Pat. No. 4,751,241 reports the use of polyglycerol esters of unsaturated fatty acids to enhance solubility of active drugs. U.S. Pat. No. 4,650,664 reports the use of acid salts of the drug and acid substances to enhance bioavailability of mopidamol. U.S. Pat. No. 4,427,648 reports the use of acid salts of the drug and acid substances to enhance bioavailability of dipyridamole. U.S. Pat. No. 4,731,360 reports the use of acylcarnitine to enhance absorption of beta-lactam antibiotics through mucous membranes. EPO Publication 119737 reports the use of cyclodextrin to enhance the bioavailability of a wide range of drugs. EPO Publication 035770 reports the use of a number of organic acids to enhance the bioavailability of glycosidic and related antibiotics. EPO Publication 192263 reports enhancing absorption of a benzoyl urea compound with cyclodextrin, polyethylene glycol or refined oil. U.S. Pat. No. 4,464,363 discloses certain aryl adjuvants as increasing the bioavailability of rectally administered insulin and other drugs. EPO Publication 65450 reports enhanced bioavailability of nifedipine with a beta-blocker. EPO Publication 164588 reports solid dihydropyridine formulations with good bioavailability containing a sparingly soluble dihydropyridine derivative with a readily water soluble filler. U.S. Pat. No. 4,704,405 reports the use of bases to enhance the bioavailability of Sulindac.
U.S Pat. No. 4,689,228 reports the use of complex carbohydrates to enhance absorption of calcium and other minerals.
Surfactants have also often been used to enhance bioavailability. U.S. Pat. No. 4,412,986 reports that nifedipine absorption is enhanced by compounding with a number of substances including surface active agents. U.S. Pat. No. 4,665,098 reports the enhancement of retinamide bioavailability using corn oil and a surfactant. U.S. Pat. No. 4,571,334 reports the use of a surfactant in the lung to enhance absorption of an anti-cancer drug. EPO Publication 031603 reports the use of surfactants to increase drug absorption, particularly 4-(monoalkylamino)benzoic acid and derivatives. U.S. Pat. No. 4,344,934 reports the use of water-soluble polymers and wetting agents to enhance solubility of drugs. EPO Publication 111841 reports the use of bile surfactants to enhance nasal absorption of LHRH agonists or antagonists. EPO Publication 292050 reports the use of surfactants to increase the bioavailability of flunarizine. EPO Publication 242643 reports the use of polysorbate-80 to decrease irritation caused by surfactant-drug preparations for nasal absorption.
The use of pro-drugs to prevent degradation and enhance absorption is another bioavailability-enhancing expedient which has been reported in the literature. EPO Publication 036534 reports hydroxyaryl or hydroxyaralkyl acid or salts, amides or esters of beta-lactam antibiotics as having increasing oral absorption. U.S. Pat. No. 4,673,534 reports sulfonic salts of carnitine have enhanced bioavailability. EPO Publication 090344 reports the use of 1,3-dioxolen-2-one derivates of drugs such as ampicillin provides greater bioavailability. EPO Publication 070013 reports the use of (5-R-2-oxo-1,3-dioxolen-4yl)methyl derivates of drugs such as antibiotics have enhanced bioavailability. U.S. Pat. No. 4,440,740 reports the use of alpha-keto aldehydes as enhancing gastro-intestinal drug absorption of numerous drugs. U.S. Pat. No. 4,443,435 reports the use of prodrugs of 6-mercaptopurine and related drugs for enhanced bioavailability. U.S. Pat. No. 4,694,006 reports acyl- or acyloxymethyl-allopurinol prodrugs having enhanced bioavailability. U.S. Pat. No. 4,747,062 reports the use of substituted benzoate ester prodrugs of betaestradiol and ethynyl estradiol for improved bioavailability. U.S. Pat. No. 4,771,073 reports the formation of L-dopa ester prodrugs to enhance bioavailability. U.S. Pat. Nos. 3,888,848 and 3,996,236 report penicillin prodrugs as having enhanced bioavailability. U.S. Pat. No. 4,021,546 report prodrug forms of digoxin having enhanced bioavailability. U.S. Pat. No. 4,058,621 reports the use of iron salts to enhance bioavailability of iron. U.S. Pat. No. 4,201,866 reports o-hemi-succinate of propanolol as a prodrug having enhanced bioavailability. U.S. Pat. No. 4,407,795 reports an inclusion compound of p-hexadecylamino benzoic acid sodium salt in beta-cyclodextrin which provides enhanced bioavailability. U.S. Pat. No. 4,722,928 describes n-oxide prodrugs of 3-hydroxy morphinans as having enhanced bioavailability. U.S. Pat. No. 4,268,441 describes prodrug forms of ketosteroidal sex hormones as having increased bioavailability.
Vasodilators have been used in combination with other drugs. In EPO Publication 106335, the use of a coronary vasodilator, diltiazem, is reported to increase oral bioavailability of drugs which have an absolute bioavailability of not more than 20%, such as adrenergic beta-blocking agents (e.g., propranolol), catecholamines (e.g., dopamine), benzodiazepine derivatives (e.g., diazepam), vasodilators (e.g., isosorbide dinitrate, nitroglycerin or amyl nitrite), cardiotonics or antidiabetic agents, bronchodilators (e.g., tetrahydroisoquinoline), hemostatics (e.g., carbazochrome sulfonic acid), antispasmodics (e.g., timepidium halide) and antitussives (e.g., tipepidine). Diltiazem has not been reported to be a gastrointestinal vasodilator. No mechanism of action is provided, and thus there is no basis for extrapolation from this disclosure that other vasodilators will act to increase bioavailability.
L. Ther and D. Winne (1971), Drug Absorption, pp. 57-69, discuss the dependence of intestinal drug absorption on blood flow. A complex relationship is described. Blood flow in the stomach and intestine is suggested as a factor in determining drug bioavailability by D.E. Cadwallader, (1971) Biopharmaceutics and Drug Interactions, (Roche Laboratories, Nutley, NJ) p. 53. At page 108 of this publication it is suggested that reserpine and quanethidine could increase the rate of absorption of orally administered drugs by increasing the blood flow to the GI tract. No experimental results were provided showing this to be the case.
A. J. McLean, et al. (1978), "Food, splanchnic blood flow, and bioavailability of drugs subject to first-pass metabolism," Clin. Pharmacol. Ther. 24:5-10, attempt to explain, via computer modeling, increased bioavailability of drugs such as propranolol or metoprolol after a meal. They predict that since not only food, but also drugs, enhance splanchic blood flow, the vasodilator hydralazine should enhance the bioavailability of propranolol or similar drugs which require metabolism through the liver to be effective. This prediction is borne out in D.W. Schneck and J.E. Vary (1984), "Mechanism by which hydralazine increases propranolol bioavailability," Clin. Pharmacol. Ther. 35:447-453, where the authors conclude that the increased bioavailability is due to hemodynamic effects. There is no disclosure or suggestion in these references that gastrointestinal vasodilators enhance bioavailability of drugs which enter the bloodstream in active form by passive diffusion.
Nicotinic acid (niacin) is a known vasodilator which causes hyperemia in many parts of the body, including the mucous membrane of the stomach. See L. Condorelli (1964), "Nicotinic Acid in the Therapy of the Cardiovascular Apparatus," Niacin in Vascular Disorders and Hvoeremia, R. Altschul (ed.), pp. 162-164. However, its effects on bioavailability have not previously been reported. Nicotinic acid is a component of Card-Colaldon.RTM. (Hoechst Corporation), which contains 0.125 mg digoxin, 400 mg pentifylline and 100 mg of nicotinic acid. This formulation is provided in a sustained-release tablet containing the nicotinic acid and pentifylline in the core, with the digoxin coated onto the tablet core. Nicotinic acid in high doses (3-6 g/day), has been used as a cardiovascular drug. See Svedmyr, N. et al. (1970), "Dose-response relationship between concentration of free nicotinic acid concentration of plasma and some metabolic and circulatory effects after administration of nicotinic acid and pentaerythritol tetranicotinate in man," in Metabolic Effects of Nicotinic Acid and its Derivatives, Gey, K.F and Carlson, L.A. (eds.), Hans Huber Publishers, pp. 1085-1098). It increases stroke volume of the heart, decreases peripheral vascular resistance and lowers low density lipids and cholesterol in the blood. As nicotinic acid is present in the Card-Cosaldon.RTM. formulation in the core of the tablet where it becomes available only after the digoxin has been solubilized, it is evident this component was not included in the formulation as a bioavailability enhancer.
The bioavailability of digoxin in the Card-Cosaldon.RTM. formulation has been studied in H.-G. Grigoleit et al. (1976) "Untersuchung zur Bioverfugbarkeit von Digoxin aus Card-Cosaldon.RTM. and alkoholischer Digoxinlosung als Standard im intraindividuellen Vergleich" ["Within-Patient Comparison Study on the Bioavailability of Digoxin from Card-Cosaldon.RTM. and from an Alcoholic Digoxin Solution as a Standard"] Therapiewoche 26:5722-5729. This study reports that the digoxin in the tablet preparation had the same bioavailability as in an alcoholic solution of digoxin alone. There is no suggestion in this article that nicotinic acid is a bioavailability enhancer, nor is any mechanism postulated to explain the bioavailability of digoxin in the tablet formulation.
Nicotinic acid has been tested in combination with sodium bicarbonate to make an effervescing tablet. N.-O Lindberg (1970), "Preparation of effervescent tablets containing nicotinic acid and sodium bicarbonate," Acta Pharm. Svecica 7:23-28. This article neither discloses nor suggests the use of nicotinic acid as a bioavailability enhancer for drugs, nor a combination of nicotinic acid with drugs which must be absorbed into the bloodstream to be active.
In 1985, A.R. Waller et al., in "Bioavailability Studies of Etofibrate in Rhesus Monkeys," Arnzeim.-Forsch./Drug Res. 35:489-492 reported that the rates and extent of bioavailability of nicotinic acid or clofibric acid administered as a mixture were similar to those of these drugs administered alone. Thus, neither drug affected the absorption of the other in rhesus monkeys. Since the mechanism of absorption of clofibric acid is not known, this article would lead me away from pursuing the line of inquiry which led to this invention.
Nicotinic acid (niacin) is present in commercial vitamin preparations in the form of niacinamides such as niacinamide ascorbate. In the niacinamide form it does not cause the vasodilation or flushing which may be experienced as a side effect to the administration of nicotinic acid per se. Nicotinic acid is a water-soluble B vitamin which is considered relatively harmless even at high dosages. See, e.g., L. R. Mosher (1970), "Nicotinic Acid Side Effects and Toxicity: A Review," Amer. J. Psychiat. 126:1290-1297. It increases peripheral blood flow. See, e.g., D.I. Abramson, et al. (1940), "Effect of Nicotinic Acid on Peripheral Blood Flow in Man," Am. J. Med. Sci. 200:96-102; R.J. Popkin (I939), "Nicotinic Acid, Its Action on the Peripheral Vascular System," Am. Heart J. 18:697-704. It increases heart rate and cardiac output, but has only minor effects on blood pressure, along with being useful in the treatment of a number of other conditions. L. Condorelli (1964) "Nicotinic Acid in the Therapy of The Cardiovascular Apparatus," Niacin in Vascular Disorders and Hyperemia, R. Altschul (ed.), pp. 156-207.
Surprisingly, although the flushing effect of nicotinic acid has been found to be reduced by the administration of acetylsalicylic acid (R.G.G. Andersson, et al. (1977), "Studies on the Mechanism of Flush Induced by Nicotinic Acid," Acta Pharmacol. et Toxicol. 41:1-10), the bioavailability of aspirin was found in the present invention to be enhanced by administration of nicotinic acid therewith. The flushing effect occurs only while the nicotinic acid plasma concentration is increasing, and disappears when the concentration reaches a constant level, however the vasodilation effect continues after the flushing has subsided. N. Svedmyr, et al. (1969), "The relationship between the plasma concentration of free nicotinic acid and some of its pharmacologic effects in man," Clin. Pharmacol. Therapeut. 10:559-570. Absorption of nicotinic acid is not affected by food ingestion. H. Bechgaard and S. Jespersen (1977), "GI Absorption of Niacin in Humans," J. Pharmaceut. Sci. 66:871-872.
Many other vasodilators are known to the art, and have been used therapeutically by themselves, i.e., not in combination with other drugs. See, e.g., M. Nickerson, (1975) "Vasodilator Drugs" in The Pharmacological Basis of Therapeutics, Chapter 34, pp. 745-760.
Bioavailabilities of drugs suitable for use in the preferred embodiments of this invention have been studied, however, not in connection with increasing bioavailability through the use of vasodilators affecting the GI tract. Some articles discussing the bioavailability of painkillers are: V. J. Stella et al. (February 1978), "Current Drug Bioavailability Information, Acetaminophen and Aspirin," Kans Pharmacy, pp. 12-13; and G. Levy et al. (1963), "Biopharmaceutical Aspects of the Gastrointestinal Absorption of Salicylates," Salicylates, An International Symposium, Dixon et al. (eds.), pp. 9-17. Articles discussing the bioavailability of theophylline are: R. Koysooko et al. (1974), "Relationship between theophylline concentration in plasma and saliva of man," Clin. Pharmacol. Therapeut. 15:454-460; G. Levy, et al. (1974), "Indirect Plasma-Theophylline Monitoring in Asthmatic Children by Determination of Theophylline Concentration in Saliva," Pediatrics 53:873-876; L. Hendeles et al. (1985), "Update on the Pharmacodynamics and Pharmacokinetics of Theophylline," CHEST 88:103S-111S; and K. M. Piafsky and R. I. Ogilvie (1975), "Dosage of Theophylline in Bronchial Asthma," New Engl. J. Med. 292:1218-1222.
It is apparent from the foregoing discussion that although vasodilators affecting the gastrointestinal tract, such as nicotinic acid, have been used alone or as components of pharmaceutical preparations for administration to patients, there has been no recognition in the art that in a formulation designed for rapid release and absorption into the bloodstream of drugs through the gastrointestinal tract via passive diffusion, such vasodilators, e.g., nicotinic acid, act to enhance the bioavailability of other drugs.